Patch-Clamp Techniques

Publication Title: 
Nature Neuroscience

Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown.

Author(s): 
Kurita, Mitsumasa
Holloway, Terrell
GarcÌa-Bea, Aintzane
Kozlenkov, Alexey
Friedman, Allyson K.
Moreno, JosÈ L.
Heshmati, Mitra
Golden, Sam A.
Kennedy, Pamela J.
Takahashi, Nagahide
Dietz, David M.
Mocci, Giuseppe
Gabilondo, Ane M.
Hanks, James
Umali, Adrienne
Callado, Luis F.
Gallitano, Amelia L.
Neve, Rachael L.
Shen, Li
Buxbaum, Joseph D.
Han, Ming-Hu
Nestler, Eric J.
Meana, J. Javier
Russo, Scott J.
Gonz·lez-Maeso, Javier
Publication Title: 
Current Topics in Medicinal Chemistry

Patch-Clamp electrophysiology, the "gold standard" for the functional study of ion channels has become automated. This innovative technology, already over a decade old, has revolutionized the strategies for the search of medicinal compounds which now can be screened at unprecedented speed, approaching the high throughput standards required by primary screening campaigns emblematic of the pharmaceutical and biotechnology industries. Consequently, an acceleration of the discovery and development of new drugs targeting ion channels is expected.

Author(s): 
Picones, Arturo
Publication Title: 
Anesthesiology

BACKGROUND: Clinical studies suggest that midazolam and propofol interact synergistically to induce hypnosis, but these drugs do not interact synergistically to prevent movement in response to noxious stimuli. The mechanisms underlying these interactions are not certain but may occur at the level of the gamma-aminobutyric acid A (GABA(A)) receptor. METHODS: The authors evaluated the interactions between propofol and midazolam in modulating GABA(A) receptor activity in embryonic hippocampal neurons.

Author(s): 
McAdam, L. C.
MacDonald, J. F.
Orser, B. A.
Publication Title: 
Journal of Neurophysiology

The ionic mechanisms that contribute to general anesthetic actions have not been elucidated, although increasing evidence has pointed to roles for subthreshold ion channels, such as the HCN channels underlying the neuronal hyperpolarization-activated cationic current (Ih). Here, we used conventional HCN1 knockout mice to test directly the contributions of specific HCN subunits to effects of isoflurane, an inhalational anesthetic, on membrane and integrative properties of motor and cortical pyramidal neurons in vitro.

Author(s): 
Chen, Xiangdong
Shu, Shaofang
Kennedy, Dylan P.
Willcox, Sarah C.
Bayliss, Douglas A.
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Ketamine has important anesthetic, analgesic, and psychotropic actions. It is widely believed that NMDA receptor inhibition accounts for ketamine actions, but there remains a dearth of behavioral evidence to support this hypothesis. Here, we present an alternative, behaviorally relevant molecular substrate for anesthetic effects of ketamine: the HCN1 pacemaker channels that underlie a neuronal hyperpolarization-activated cationic current (I(h)).

Author(s): 
Chen, Xiangdong
Shu, Shaofang
Bayliss, Douglas A.
Publication Title: 
Anesthesiology

BACKGROUND: It is well documented that several general anesthetics, including propofol, potentiate glycine receptor function. Furthermore, glycine receptors exist throughout the central nervous system, including areas of the brain thought to be involved in sleep. However, the role of glycine receptors in anesthetic-induced hypnosis has not been determined. METHODS: Experiments were conducted in rats where the loss of righting reflex (LORR) was used as a marker of the hypnotic state.

Author(s): 
Nguyen, Hai T.
Li, Ke-yong
daGraca, Ralph L.
Delphin, Ellise
Xiong, Ming
Ye, Jiang H.
Publication Title: 
Anesthesia and Analgesia

BACKGROUND: Volatile aromatic compounds such as benzene are general anesthetics that cause amnesia, hypnosis, and immobility in response to noxious stimuli when inhaled. Although these compounds are not used clinically, they are frequently found in commercial items such as solvents and household cleaning products and are abused as inhalant drugs. Volatile aromatic anesthetics are useful pharmacological tools for probing the relationship between chemical structure and drug activity at putative general anesthetic targets.

Author(s): 
Solt, Ken
Kelly, Elizabeth W.
Cotten, Joseph F.
Raines, Douglas E.
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

General anesthetics cause sedation, hypnosis, and immobilization via CNS mechanisms that remain incompletely understood; contributions of particular anesthetic targets in specific neural pathways remain largely unexplored. Among potential molecular targets for mediating anesthetic actions, members of the TASK subgroup [TASK-1 (K2P3.1) and TASK-3 (K2P9.1)] of background K(+) channels are appealing candidates since they are expressed in CNS sites relevant to anesthetic actions and activated by clinically relevant concentrations of inhaled anesthetics.

Author(s): 
Lazarenko, Roman M.
Willcox, Sarah C.
Shu, Shaofang
Berg, Allison P.
Jevtovic-Todorovic, Vesna
Talley, Edmund M.
Chen, Xiangdong
Bayliss, Douglas A.
Publication Title: 
Anesthesiology

BACKGROUND: Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the ?-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile. METHODS: The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons.

Author(s): 
Egan, Talmage D.
Obara, Shinju
Jenkins, Thomas E.
Jaw-Tsai, Sarah S.
Amagasu, Shanti
Cook, Daniel R.
Steffensen, Scott C.
Beattie, David T.
Publication Title: 
Anesthesia and Analgesia

BACKGROUND: Carboetomidate is an etomidate derivative that produces hypnosis without inhibiting adrenal corticosteroid synthesis. Similar to etomidate, carboetomidate modulates ?-aminobutyric acid type A receptors, but its effects on other ion channel targets of general anesthetics are unknown. METHODS: We compared etomidate and carboetomidate effects on human N-methyl-d-aspartate receptors or neuronal nicotinic acetylcholine receptors (nnAChRs) expressed in Xenopus oocytes, using 2-microelectrode voltage clamp electrophysiology.

Author(s): 
Pierce, David W.
Pejo, Ervin
Raines, Douglas E.
Forman, Stuart A.

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